There is little extant data concerning how sex may modulate the magnitude of opioid-induced immunomodulation. The present proposal addresses this important issue by extending the recently-identified finding that morphine and other mu-opioids produce significantly greater enhancement in female than male rats, of contact hypersensitivity (CHS), a cutaneous form of delayed-type hypersensitivity. Specific Aim I tests the hypothesis that morphine administered prior to the challenge phase of CHS induces sexually dimorphic effects on key mediators of CHS, including cytokine expression and T-lymphocyte infiltration. To that end, animals will be sacrificed at selected times following antigen challenge and the extent of CD4( and CD8( T-lymphocyte infiltration will be quantified by immunohistochemistry. To assess which molecular mediators are differentially expressed in males and females, cytokine levels will be quantified by Real-Time RT-PCR. Specific Aim II tests the hypothesis that kappa and delta opioids also produce differential effects on CHS in males and females through their activity at CNS opioid receptors. This aim will employ intracranial cannulation, drug microinjection techniques, and receptor antagonism to address this important issue. Specific Aim III will assess the role of a putative key hormonal determinant of observed sex differences by determining the effect of estradiol replacement in ovariectomized female rats on morphine's modulation of the CHS response. Together, these investigations will provide novel data concerning mechanisms of sexually dimorphic modulation of the clinically-relevant CHS response by a range of opioid drugs.